Multiple sclerosis (MS) is an inflammatory disease of the central nervous system that afflicts approximately 400,000 people in the United States alone. Currently there is no cure for MS and only seven disease-modifying drugs have been approved by the FDA to treat relapsing, but not primary progressive, forms of MS. Although the genetic and environmental factors that trigger the disease vary, the common pathological outcome of MS is the destruction of oligodendrocytes and their associated neuronal axons through a process called encephalomyelitis. Development of encephalomyelitis requires coordinated expression of a unique class of genes called inflammatory genes. These genes encode inflammatory proteins that mediate the activation, migration, and effector function of inflammatory cells that cause encephalomyelitis. Inhibiting the functions of this class of genes may be effective for ameliorating MS. However, because MS is mediated by many, if not all, inflammatory genes, inhibiting one or a few of them may have limited efficacies. This competitive renewal application is inspired by our recent discovery that the transcription factor c Rel, a lymphoid and myeloid member of the Rel/nuclear factor-B (NF-B) family, controls (i) the expression of multiple inflammatory genes, and (ii) the development of the inflammatory Th17 cells. The goal of this application is to elucidate the mechanisms through which c-Rel controls the Th17 response, and to develop c-Rel-blocking drugs for the treatment of inflammatory diseases. The hypotheses to be tested are: (i) c-Rel is a primary transcription factor of the Th17 response, and (ii) c-Rel is a prime drug target for treating multiple sclerosis. PUBLIC HEALTH RELEVANCE: Information generated from these studies will not only advance our understanding of the Th17 and c-Rel biology, but also aid in developing novel c-Rel blocking drugs for the treatment of inflammatory diseases. Therefore, this project may advance both scientific knowledge and clinical practice.